Summary. Idiopathic inflammatory myopathies (IIM) are autoimmune disease characterized by chronic muscle weakness and inflammation. Juvenile dermatomyositis (JDM), adult-onset dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM) are major subgroups of IIM. In pathognomonic muscle biopsies of JDM and DM, there are remarkable perivascular inflammation with complement- mediated destruction of perivascular endothelium, leading to perifascicular ischemia and degeneration of muscle fibers. However, the triggers for complement activation and whether complement is engaged in the breakdown of immune tolerance in IIM have not been defined. A great impeding factor for research progress of IIM is the low prevalence of the disease and therefore statistical power of analysis becomes an issue. The International Myositis Genetic Consortium (MYOGEN) was created to facilitate and advance collaborations on genetic studies of IIM. Through application of immunochip for genotyping of MYOGEN samples of IIM patients, it has been shown that HLA-DRB1*03:01 of the ancestral haplotype AH8.1 in Caucasians is the strongest risk factors for all forms of IIM. Among European subjects, the presence of HLA-DRB1*03:01 is strongly associated with complement C4A deficiency. There are multiple layers of genetic diversity for complement C4, including multi-allelic gene copy number variations (CNVs) and gene size dichotomy for its two isotypes, acidic C4A and basic C4B. Through a meticulous pilot study, we have shown that C4A deficiency is a very strong and independent genetic risk factor for JDM, including under the presence of DRB1*03:01 (DR3+). Therefore, it would be of great interest to decipher the roles of C4-CNVs and C4A deficiency in various forms of inflammatory myopathies from the MYOGEN. The specific aim is ?To investigate the MHC complement genetic variants in disease susceptibility and pathogenesis of idiopathic inflammatory myopathies.? We will evaluate complement C4-CNVs and associated polymorphisms for C4A and C4B, plus nonsense mutations of MHC-linked complement genes, in the context of their linkage disequilibrium (LD) with specific HLA-DRB1 genotypes, on various forms of IIM from the MYOGEN (N=2566). Race matched control population with >1571 subjects is from our own collection. We will dissect the independent roles of HLA-DRB1 variants, C4-CNVs and C4A deficiency on disease risks of IIM and its sub-types. We will extend the project to a longitudinal study of local JDM patients through measuring the cell-bound levels of processed complement activation products that may yield insights on the mechanism of disease pathogenesis, and as a convenient biomarker for IIM disease activities. Health related significance. Successful execution of this proposal will advance our knowledge on the genetic risk factors and mechanism of pathogenesis for JDM, DM, PM and IBM. The results obtained would help creating better strategies for diagnosis, prognosis, management and therapies of myositis